Outcomes of Spatially Fractionated Radiotherapy (GRID) for Bulky Soft Tissue Sarcomas in a Large Animal Model

Abstract

GRID directs alternating regions of high- and low-dose radiation at tumors. A large animal model mimicking the geometries of human treatments is needed to complement existing rodent systems (eg, microbeam) and clarify the physical and biological attributes of GRID. A pilot study was undertaken in pet dogs with spontaneous soft tissue sarcomas to characterize responses to GRID. Subjects were treated with either 20 Gy (3 dogs) or 25 Gy (3 dogs), delivered using 6 MV X-rays and a commercial GRID collimator. Acute toxicity and tumor responses were assessed 2, 4, and 6 weeks later. Acute Radiation Therapy Oncology Group grade I skin toxicity was observed in 3 of the 6 dogs; none experienced a measurable response, per Response Evaluation Criteria in Solid Tumors. Serum vascular endothelial growth factor, tumor necrosis factor α, and secretory sphingomyelinase were assayed at baseline, 1, 4, 24, and 48 hours after treatment. There was a trend toward platelet-corrected serum vascular endothelial growth factor concentration being lower 1 and 48 hours after GRID than at baseline. There was a significant decrease in secretory sphingomyelinase activity 48 hours after 25 Gy GRID ( P = .03). Serum tumor necrosis factor α was quantified measurable at baseline in 4 of the 6 dogs and decreased in each of those subjects at all post-GRID time points. The new information generated by this study includes the observation that high-dose, single fraction application of GRID does not induce measurable reduction in volume of canine soft tissue sarcomas. In contrast to previously published data, these data suggest that GRID may be associated with at least short-term reduction in serum concentration of vascular endothelial growth factor and serum activity of secretory sphingomyelinase. Because GRID can be applied safely, and these tumors can be subsequently surgically resected as part of routine veterinary care, pet dogs with sarcomas are an appealing model for studying the radiobiologic responses to spatially fractionated radiotherapy.

Keywords: ablative; abscopal; canine; endothelial; microenvironment.

Figure 1.

Measured GRID factor as a function of treatment field size (cm²) at isocenter (d = D_max) for 6 MV X-rays on a Novalis TX linear accelerator using a brass GRID collimator. For a given field size (in area) and GRID treatment dose, the monitor units are calculated using the GRID factor curve, above. We have explored different formats of GRID field factor as a function of treatment portal sizes, including equivalent square field size, and total area of the field size for a range of field sizes and shapes we anticipated to use for the GRID therapy in dogs. We found that the GRID factor and field size in area capture the most stable relationship, of all tested.

Figure 2.

A 6-MV GRID field (25 cm × 24 cm) beam profile. The dose profile is measured at D_max using Gafchromic RTQA-2 film. The film density is converted to dose using a film density calibration curve based on ion chamber data in conventional (non-GRID) fields.

Figure 3.

Percentage depth dose (PDD) of the 6-MV photon 15 cm × 15 cm GRID filed, through the central opening of the GRID collimator. The GRID factor is defined as the ratio of dose at D_max of a GRID field of given size and dose at D_max of a 10 × 10 cm field under machine output calibration condition, times the machine output factor of 1 cGy/MU. We determined the relative dose ratio by measuring the dose on the central diode detector of a MapCHECK array system from a given GRID field radiation and a 10 × 10 cm field radiation under the same setup (100 cm SSD, central axis, with no additional build-up). We assumed that the depth difference between 6 MV D_max (1.5 cm) and the measurement depth (2 cm) has negligible effect on the relative GRID factor measurement. SSD = Source to surface distance.

Figure 4.

Example of a GRID treatment plan for the same dog that is shown in Figure 5. Dose is depicted via relative isodose lines on a parasagittal image (left: correlating with the beams-eye view) and an axial image (right) wherein the blue arrow indicates the beam’s axis; the tumor is located on the cuadolateral thigh, and anatomic orientation is provided (eg, caudal, distal). The gross tumor volume is outlined in red.

Figure 5.

Photograph of grade I skin toxicity (focal alopecia on the lateral aspect of the thigh, where the GRID collimated radiation exited the body).

Figure 6.

Platelet-corrected concentration of vascular endothelial growth factor (VEGF) as a function of time after irradiation, depicted using a box and whisker plot.

Figure 7.

Secretory sphingomyelinase (S-SMase) activity as a function of time after irradiation; error bars depict the standard deviation of the mean.